Background: A marked inflammatory response in necrotising soft-tissue infection (NSTI) may contribute to the severe clinical course. Intravenous polyspecific immunoglobulin G (IVIG) is used by some as adjuvant treatment for NSTI, but in the randomised INSTINCT trial, no effect of IVIG in NSTI patients was seen on physical quality of life. In experimental studies, IVIG may induce immunosuppressive effects by reducing the pro-inflammatory response and neutralising circulating superantigens. However, data on the potential immunomodulatory effects are sparse and remain to be investigated in a clinical setting. In this post hoc analysis of the INSTINCT trial, we aimed to assess the effect of IVIG on various inflammatory cytokines up to day 3 after randomisation. Methods: Tumour necrosis factor (TNF), interleukin-1β, interleukin-6, interleukin-10 and granulocyte colony-stimulating factor were measured at admission, days 1, 2 and 3. Results: A total of 100 ICU patients with NSTI were included; 50 were allocated to IVIG (25 g/d for 3 days) and 50 to placebo. No difference in the overall inflammatory response was observed between groups except from TNF, which was higher in the IVIG group as compared to the placebo group (area under curve-admission to day 3, 93.6 vs 60.2, P =.02). Similarly, no differences were observed in percentage change from baseline to day 3 in any of the studied cytokines between patients allocated to IVIG group and those allocated to placebo group. Conclusion: In ICU patients with NSTI, IVIG did not reduce the plasma concentration of cytokines in the first 3 days.